Abstract

Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.

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Acknowledgements

Asm-deficient mice and asm-1–deficient worms were provided by R. Kolesnick, Memorial Sloan Kettering Cancer Hospital, and E2A-Cre mice by R. Waldschütz, University Hospital Essen. The G4 antibody against Asm was provided by K. Sandhoff, University of Bonn. We thank S. Harde, B. Wilker, C. Sehl, S. Keitsch, M. Schäfer, S. Müller and E. Naschberger for excellent technical help and F. Lang for valuable discussion. Parts of the work were supported by funding from Deutsche Forschungsgemeinschaft grants GU 335/23-1, KO 947/11-1 and GRK 1302.

Author information

Affiliations

  1. Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.

    • Erich Gulbins
    • , Monica Palmada
    • , Christoph Böhmer
    • , Katrin A Becker
    •  & Heike Grassmé
  2. Department of Surgery, University of Cincinnati, Cincinnati, USA.

    • Erich Gulbins
  3. Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.

    • Martin Reichel
    • , Davide Amato
    • , Christian P Müller
    • , Carsten H Tischbirek
    • , Teja W Groemer
    • , Philipp Tripal
    • , Sven Staedtler
    •  & Johannes Kornhuber
  4. Institute of Nutritional Sciences, University of Potsdam, Potsdam, Germany.

    • Anja Lüth
    •  & Burkhard Kleuser
  5. Department of Neurology, University Hospital Zurich, Zurich, Switzerland.

    • Ghazaleh Tabatabai
    •  & Michael Weller
  6. Neuroscience Center Zurich, Zurich, Switzerland.

    • Ghazaleh Tabatabai
  7. Department of Physiology I, University of Tübingen, Tübingen, Germany.

    • Teresa F Ackermann
  8. Institute of Physiology and Pathophysiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.

    • Johannes van Brederode
    •  & Christian Alzheimer
  9. Department of Psychiatry and Psychotherapy, University Hospital Basel, Basel, Switzerland.

    • Undine E Lang

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Contributions

E.G. and J.K. initiated the studies, designed experiments and supervised research. E.G., J.K. and M.W. wrote the manuscript. E.G. also performed most mouse studies. E.G., K.A.B. and G.T. performed the histological studies and developed the polyclonal Asm-specific antibody. M.P. and C.B. performed the C. elegans studies. A.L. and B.K. measured ceramide concentrations by mass spectrometry. M.W. designed some experiments and participated in BrdU stainings. H.G. performed the confocal microscopy studies. J.K., P.T. and S.S. performed experiments on the concentration-dependent inhibition of ASM by antidepressant drugs. M.R. and M.P. performed experiments on 5-HT uptake in cultured hippocampal neurons. M.R. and J.K. performed experiments on 5-HT uptake in mouse brain synaptosomes. C.H.T. and T.W.G. designed and performed synapse staining and confocal analyses. T.F.A., U.E.L. and E.G. performed behavioral experiments. C.P.M., D.A., M.R. and J.K. designed and performed hippocampal injection and microdialysis studies. C.A., J.v.B., M.R. and J.K. designed and performed electrophysiological studies in hippocampal slices. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Erich Gulbins or Johannes Kornhuber.

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DOI

https://doi.org/10.1038/nm.3214

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